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www.biopharminternational.com July 2021 BioPharm International eBook 7 that advances in liquid chromatogra- phy (LC) and CE have had significant impact on biopharmaceutical develop- ment by improving method robustness and throughput. "There was a time when scientists had to identify all peaks in a peptide map using Edman degradation—a tedious task with limited sensitivity and robustness—but now the peptide sequence can be easily elucidated via LC–MS. Beyond this, peptide-based multi-attribute method (MAM) as an emerging technology has the potential to offer enhanced sensitivity and selec- tivity for the simultaneous detection and quantification of multiple product attributes, even in the quality control (QC) laboratory," Huang says. For binding assays, Huang says, surface plasmon resonance and bio- layer interferometry technologies have become increasingly promising com- pared with the conventional enzyme- linked immunosorbent assay binding method and have been used in both biologics development and qua lit y control labs. WHAT THE INDUSTRY STILL NEEDS Moving forward, the increasing com- plexity of biologic modalities in drug development may also lead to analyti- cal needs not yet met by current meth- ods. "The field of complex biologicals is diverse and expanding rapidly," says Hersch. "Standardization of analyt- ical requirements for full character- ization and quality control of these new modalities is, in some cases, still evolving and represents an important unmet need." According to Hersch, unmet need in the industry includes quality con- trol analyses for the newest autolo- gous cell therapy approaches, which must be performed quickly to ensure the shortest possible vein-to-vein time for critically ill patients. "To meet this need, researchers may have to rely more on faster NGS-based methods rather than more time-consuming traditional in-vivo procedures," she envisions. In addition, as biologic modalities become increasingly complex (e.g., bispe- cific antibodies, gene therapies, cell ther- apies), there will be a continued need to develop methods for characterization of the active biologics' components, says Fitzgibbons. This development may involve analytical techniques that are only just now becoming widely used. "As new higher-resolution analytical tech- niques and more hybridization occurs within instrumentation, new opportu- nities for characterization present them- selves," he states. One example of instrument hybrid- ization involves the combination of CE techniques with MS, Fitzgibbons says. With hybridization such as this, identif ication of size or charge het- erogeneit y prof iles becomes much more straightfor ward, he notes. He also says that analytical instrumen- tation that automates processes that were previously undertaken manually offers higher throughput and opens the way for new regulatory require- ments for analytical characterization. "Additionally, as the development in viral vector manufacturing progresses, and as new gene therapy offerings are developed, new analytical challenges arise to assure CQAs are understood and controlled," he adds. M e a n w h i l e , o n-l i n e /r e a l-t i m e mon itor i ng of produc t at t r ibute s has gained increasing interest due to advancement in continuous processing for biologics manufacturing in recent years, says Huang. He also adds that a greater level of automation in sample preparation as well as applying MS techniques, such as peptide-based MAM, which has been used in qual- it y control to simultaneously moni- tor different product attributes, can greatly enhance real-time monitoring and expedite biologics development. "One gap that needs addressing is industr y coalescence in developing standardized methods and reagents," adds Colangelo. He points out that many manufacturers still develop fit- for-purpose methods for each biother- apeutic, which leads to a continual reinvention of the analytical methods for every new drug product. Bunce points out that capacity is a major issue because all providers are looking to access platforms that can express more material in less volume, while maintaining the sensitivity of the process at scale. "Consequently, the industry needs to ensure that the analytical tools and methods are f it- for-purpose and will robustly inform the maintenance of the overall integ- rity and stability of the biopharmaceu- tical," he says. Bunce also stresses that it is imper- ative to get the analy tical strateg y and methodologies right in the early stages to support conf idence in the results and mitigate issues with quality downstream. "Paying attention early on is crucial to long term success of the biologic and mitigates risk of cor- recting issues at later stages of devel- opment, which may have an impact both in terms of economics and safety to the patients. Getting things right up front is a mindset to be encouraged in ana ly tica l method development to characterize biopharmaceutica ls and reduce risk in the drugs that we develop," he asserts. Marc Wolman, principal scientist at PPD Laboratories' GMP Lab, mean- while, explains that the biopharma- ceutical industry has made significant strides in managing logistics and work- ing within critical timelines, which has been especially and recently evi- denced by the successful development, production, analyzation, and review of new pharmaceutical products in record time to battle COVID-19. "However, we also saw that drug sponsors, raw material and testing reagent suppliers, CDMOs [contract development and manufacturing organizations], CROs [contract research organizations], and regulatory agencies have the opportu- Biopharmaceutical Analysis Analytical Evolution